Pressor amines



PRESSOR AMINES Ellis Rex Pinson, Jr., and Gerald D. Laubach, JacksonHeights, N. L, assignors to Chas. Pfizer & (10., Inc., New York, N. Y.,a corporation of Delaware No Drawing. Application January 27, 1955,Serial No. 484,562

8 Claims. (Cl. 167-65) This invention is concerned with certaincompositions which are novel and of particular value for treatment ofcertain conditions of the human body. In particular, it is concernedwith new compositions of pressor amines and acid esters ofl4a-hydroXy-hydrocortisone which are of value as therapeutic agents,particularly for treating nasal congestion and inflammation.

A variety of agents have been proposed and used as nasal decongestantsin the treatment of various conditions associated with respiratoryinfections and colds. Many of these have had a limited value, but oftenrelief is only temporary and of a limited nature.

The present invention is concerned with a group of compositions ofpressor amines with acid esters of 14ahydroxy-hydrocortisone in whichthe 14a-hydroxy-hydrocortisone molecule is substituted at the21-position with a polycarboxylic acid group having at least one freecarboxylic acid radical. Such acid esters of l4a-hydroxyhydrocortisoneare described and claimed in copending patent application Serial No.476,556, filed on December 20, 1954, by Gilbert M. Shull et a1.

As indicated above, the compositions which are an object of the presentinvention are prepared from the acid esters of14a-hydroxy-hydrocortisone and various pressor amines. These pressoramines are members of the class of therapeutic agents known asvasoconstrictors. Among amines which are useful for this purpose areephedrine, amphetamine (chemically designated as 1- phenyl-Z-arninopropane), phenylephrine, epinephrine,2-(l,2,3,4-tetrahydronaphthyl)-imidazoline, Z-aminoheptane,2-(1-indanyl)-imidazoline, and a variety of other such compounds wellknown in the field of pharmaceutical chemistry. Particularly useful arethose which have a minimum efifect upon the central nervous system andheart. This is a property which is readily determined and the preferablepressor amines may be readily-selected.

The amine-carboxylic acid compositions which are an object of thisinvention may be prepared simply by mixing the desired carboxylic acidester of 14a-hydroxyhydrocortisone with the chosen pressor amine. Uponaddition of the mixture or the individual components of the compositionto a suitable liquid medium, salt formation between the acid and basewill result. The extent of such reaction will depend upon the proportionof the two components and the nature of the medium. In general, fromabout one mole of pressor amine to about five moles may be combined withfrom five to one moles of l4a-hydroXy-hydrocortisone ester. If it isdesired to convert the materials completely to the salts, this may bedone. For instance, equimolecular proportions of the two compounds maybe contacted in water or in a solvent such as a lower (one to fourcarbon) alcohol (e. g. methanol, ethanol, isopropanol), ketone, orhalogenated hydrocarbon (e. g. chloroform, carbon tetrachloride,trichloroethylene) (e. g. acetone, methyl ethyl ketone). The salt thatis formed either separates or may be recovered by removal of thesolvent, for instance, by evaporation. In general, it is advisable touse approximately nited States Patent "ice equimolecular proportions inpreparing the salts. However, the use of an excess of either one of thematerials in the form of one of its simple salts (e. g. the sodium saltof a 21-acid ester of 14a-hydroxy-hydrocortisone or the hydrochloride ofa pressor amine) is not disadvantageous. If a free pressor amine and afree acid ester of 14a-hydroXy-hydrocortis'one are used, it ispreferable to use them in approximately equimolecular proportions toobtain appreciable water solubility. Salt formation solubilizes each ofthe materials. The salts that are formed by this reaction usually havesufilcient solubility in pharmaceutically-acceptable vehicles which areused for administration of therapeutic agents to the nasal passages sothat the compounds may be prepared in such vehicles for readyadministration. Alternatively, a suspension may be used. In fact, it isnot essential that the salt be isolated, but the compound may beprepared from the chosen amine and carboxylic acid reactants in a mediumsuitable for application in therapy. Aqueous solutions of thetherapeutic agents are favored, but various other vehicles, such aspropylene glycol or mixtures of this with water, and non-toxic alcohols(having two or three carbon atoms) diluted with water may also be usedfor this purpose. Rather than using the amine and the carboxylic acidester of l4u-hydroXy-hydrocortisone, it is possible to use a salt ofeach of the components. (In fact, this is preferable if other thanequimolecular proportions are used.) Thus, the sodium salt of the acidsuccinate of 14a-hydroxy-hydrocortisone may be mixed in aqueous solutionwith the hydrochloride .of epinephrine. The byproduct sodium chloridewhich is formed is notin any Way deleterious and may either be removedor left in the reaction mixture which is then used for the preparationof a nasal decongestant composition. If such a reaction is conducted ina solvent such as absolute ethanol, the sodium chloride may be removedby filtration and the desired amine salt may be recovered by evaporationof the solvent or the alcoholic solution may bediluted with water foruse. One of the distinct advantages of the compositions of thisinvention (and :by compositions we include salts as well as mixtures) isthe higher aqueous solubility of many of these compositions as comparedto 14a-hydroxy-hydrocortisone or l4a-hydroxyhydrocortisone acetate. Thehigh solubility makes for more convenient administration as atherapeutic agent.

The compositions of the present invention are used as dilute solutionsin various .pharmaceutically-acceptable media as indicated'above. Theconcentration of these solutions may range from 0.05 percent to about 3percent by weight. Various other materials may be present in thesolutions, including stabilizers such as sodium bisulfite or sodiumformaldehyde sulfoxylate. Certain other materials which impart apleasant odor to the compositions may also be used. However, it shouldbe realized that these are not essential components of the therapeuticcompositions.

The compositions'of the present invention are, as indicated above, ofparticular value for treatment of various conditions of nasal passagesto assure rapid and prolonged decongestion. The compositions are alsovery effective in alleviating inflammation and irritation of the nasalpassages which often accompany congestion associated with colds. The twocomponents that are used in the preparation of the salts do notindividually serve to give such an unusual measure of relief for suchconditions, that is, there seems to be a definite coaction between thecomponents. Furthermore, the physical properties of the salts aredefinitely advantageous in that many of them dissolve at suitableconcentrations in media useful for administration of therapeutic agentsto the nasal passages. The compositions also possess a desirable degreeof stability, such that the liquid solutions of the appended claims.

these materials may be prepared and used without undue degradation ofthe normally sensitive 14a-hydroxy-hydrocortisone compounds. 7In'copending application Serial No. 451,946, filed on August 24,1954,there is idescribedand claimed compositions of pressor amines and of21-acid esters of hydrocortisone. The compositions of this presentinvention have. advantages o'ver the compositions there claimed. Theseadvantages lie in the fact that the. anti-inflammatory action of the14a-hydroxy-hydrocortisone compositions is more highly specific than isthe action of the hydrocortisone compositions. When the compositions areused over a prolonged period, another advantage lies in the fact thatthe compositions of this present invention have fewer side effects uponthe metabolism of salt and water, and also fewer androgenic sideeffects.

The following examples are given by way of illustration and are not tobe considered as the sole embodiment of this invention. It is to heunderstood that protection hereof is only to be limited by the specificwording of Example I A solution of 0.01 mole of14a-l1ydroxy-hydrocortisone 21-acid phthalate in a small volume ofisopropanol was added to a solution of 0.01 mole of ephedrine in a smallvolume of isopropanol. The mixture was allowed to stand overnight andthe. solvent was evaporated by heating on a steam bath. The crystallinesalt was dried under vacuum. A 0.2 percent solution of the salt in waterwas prepared. It was found useful as an anti-inflammatory nasaldecongestant.

Example 111 A solution of 0.1 mole of phenylephrine hydrochloride in asmall volume of water was treated with an equimolecular proportion ofthe sodium salt of 14u-hydroxy hydrocortisone21-(3,6-endomethylene-hexahydrophthalic acid) ester. The aqueous mixturewas diluted to such an extent that a 0.2 percent by weight concentrationof the amine-carboxylic acid salt was obtained. This composition wasfound to be an excellent nasal decongestant.

Example IV A mixture of 1 mole of methamphetamine hydrochloride (alsochemically referred to as alpha-l-phenyl-Z- methylaminopropanehydrochloride) and 0.2 mole of the sodium salt of14a-hydroxy-hydrocortisone Zl-acid glutarate was prepared. When anaqueous was prepared with a total concentration by weight of 0.1 percentof the mixture, it was found to be an efiective nasal decongestant,rapidly alleviating irritation of the nasal mucosa.

Example V A mixture of 0.1 mole of methamphetamine hydrochloride and0.05 mole of the sodium salt of the 2l-acid succinate of14a-hydroxy-hydrocortisone was prepared. Small portions of this mixturewere placed in bottles with medicine dropper caps. Addition ofsufiicient water to form a 0.2 percent by weight solution, yielded anunusually effective nasal decongestant.

What is claimed is:

l. A salt of a 2lhydrocarbon dicarboxylic acid ester of 14alpha-hydroxy-hydrocortisone selected from the group consisting of 14alpha-hydroxy-hydrocortisone 21- acid succinate, l4alpha-hydroxy-hydrocortisone 21-acid phthalate, l4alpha-hydroxy-hydrocortisone 21-(3,6-endomethylene-hexahydrophthalicacid) ester, and 14 alphahydroxy-hydrocortisone 21-acid glutarate with apressor amine selected from the class consisting of ephedrine, 1- phenyl2-amin0propane, alpha-l-phenyl-Z-methylaminopropane, phenylephrine,epinephrine, and 2 (1,2,3,4- tetrahydron aphthyl) -imidaz oline.

2. A pharmaceutical composition which comprises essentially a dilutesolution in a pharmaceutically acceptable vehicle of a salt of a2lhydrocarbon dicarboxylic acid ester of 14 alpha-hydroxy-hydrocortisoneselected from the group consisting of 14 alpha-hydroxy-hydrocortisone2l-acid succinate, l4 alpha-hydroxy-hydrocortisone 2l-acid phthalate, l4alpha-hydroxy hydrocortisone 2l- (3,6-endomethylene-hexahydrophthalicacid) ester, and 14 alpha-hydroxy-hydrocortisone 2l-acid glutarate witha pressor amine selected from the class consisting of ephedrine,1-phenyl-'2-aminopropane, alpha-l-phenyl- 2-methylaminopropane,phenylephrine, epinephrine, and 2-( 1,2,3,4-tetrahydronaphthyl)-imidazoline.

3. A process for the preparation of a pharmaceutical compound whichcomprises contacting in an inert liquid medium a 2lhydrocarbondicarboxylic acid ester of 14 alpha-hydroxy-hydrocortisone selected fromthe group consisting of 14 alpha-hydroxy-hydrocortisone '21-acidsuccinate, 14 alpha-hydroxy-hydrocortisone 21 -acid phthalate, 14alpha-hydroxyhydrocortisone 21-(3,6-endomethylene-hexahydrophthalicacid) ester, and 14 alphahydroxy-hydrocortisone 21-acid glutarate andapressor amine selected from the class consisting of ephedrine,l-phenyl-Z-aiminopropane, alpha-I-phenyI-Z-methylarninepropane,phenylephrine, epinephrine, and 2-( l,2,3,4-tetrahydronaphthyl)-imidazoline.

4. A compound as claimed in claim 1 wherein the pressor amine isphenylephrine.

' 5. A compound as claimed in claim 1 wherein the pressor amine is2(1,2,3,4-tetrahydronaphthyl)-imidazoline.

6. A compound as claimed in claim 1 wherein the hydroxy-hydrocortisoneester is the acid succinate.

7. A compound as claimed in claim 1 wherein the14mhydroxy-hydrocortisone ester is the acid phthalate.

8. The salt of 2-(1,2,3,4-tetrahydronaphthyl) imidazoline and the21-acid succinate of 14u-hydroxy-hydrocortisone. 7

References Cited in the file of this patent

1. A SALT OF A 21-HYDROCARBON DICARBOXYLIC ACID ESTER OF 14ALPHA-HYDROXY-HYDROCORTISONE SELECTED FROM THE GROUP CONSISTING OF 14ALPHA-HYDROXY-HYDROCORTISONE 21 ACID SUCCINATE, 14ALPA-HYDROXY-HYDROCORTISONE 21-ACID PHTHALATE, 14ALPHA-HYDROXY-HYDROCORTISONE 21-(3,6-ENDOMETHYLENE-HEXABHYDROPTHALICACID) ESTER, AND 14 ALPHAHYDROXY-HYDROCORTISONE 21-ACID GLUTARATE WITH APRESSOR AMINE SELECTED FROM THE CLASS CONSISTING OF EPHEDRINE, 1PHENYL-2-AMINOPROPANE, ALPHA-1-PHENYL-2-METHYLAMINOPROPANE, PHENYLEPHRINE,EPINEPHRINE, AND 2- (1,2,2,4TETRAHYDRONAPHTHYL)-IMIDAZOLINE.